Radiolabeled proteins have been investigated extensively over the past decade for a number of clinical applications. For example, radiolabeled monoclonal antibodies are being developed for therapeutic and diagnostic uses. Monoclonal antibodies having high specificity and affinity for antigens on tumor cell surfaces are considered desirable candidates as carrier molecules to which specific radionuclides can be attached for delivery of radioactivity to a cancer site for therapy or diagnosis.
Radiohalogens are known to possess utility in both therapy and diagnosis. For example .sup.123 I has been proven useful for imaging, while .sup.131 I can be used for imaging and more preferably for radiotherapy. Bromine radionuclides .sup.75 Br and .sup.76 Br are also useful in diagnosis, while .sup.77 Br is used in radiotherapy. Fluorine-18 (.sup.18 F) and astatine-211 (211At) are also utilized in diagnostics and radiotherapy.
Processes for directly labeling proteins, such as antibodies, have proven to be difficult. Typically, the strong oxidation conditions involved in direct radiolabeling of an antibody have substantial adverse effects on the biological activity of the antibody. It is also known that radiohalogenation of antibodies occurs primiarily at the tyrosyl residues providing a less than stable bond. In vivo dehalogenation, rendering the imaging or therapeutic agent useless and causing possible toxicity to the patient may result.
Improvements have been realized with the development of indirect labeling techniques. These involve the prelabeling of a small molecule suitable for subsequent conjugation to a protein. An early series of small molecules useful for indirect labeling includes a phenol group for facile introduction of the radiohalogen. The exemplary member of this group is the commercially available Bolton-Hunter reagent ##STR2##
While these reagents greatly reduce the protein-damaging chemistry used in the direct labeling techniques, in vivo deiodination is still a problem. More recent reagents for indirect labeling include succinimidyl para-iodobenzoate ##STR3## and succinimidyl para-iodophenylpropionate ##STR4##
U.S. Pat. No. 4,885,153 discloses indirect radiohalogenating reagents of the formula EQU *X--Ar--R
where *X is a radiohalogen, Ar is an aromatic or heteroaromatic ring which may include polar substituents, e.g., nitro, sulfonic acid, carboxylic acid or dialkylamino, and R is a short chain substituent which includes a functional group for conjugation to a protein.